(150 days)
No
The device description details automated image acquisition and presentation to the user for final classification, but does not mention any AI/ML algorithms for image analysis or classification. The decision-making process for classifying an event as a tumor cell is based on predefined morphological and phenotypic criteria applied by the user.
No
The device is an in vitro diagnostic (IVD) tool used for enumerating circulating tumor cells to monitor metastatic breast cancer. It does not provide treatment or alter the patient's body in any way, which is characteristic of therapeutic devices.
Yes
The device is intended for the enumeration of circulating tumor cells (CTC) and its presence is associated with decreased progression-free survival and overall survival in patients with metastatic breast cancer. It is explicitly stated that "The test is to be used as an aid in the monitoring of patients with metastatic breast cancer." This indicates its role in providing information for clinical assessment and management, which defines a diagnostic device.
No
The device description clearly outlines physical components like reagents, nanoparticles, cartridges, and analyzer systems (CellTracks AutoPrep®, MagNest®, CellTracks® Analyzer II, CellSpotter® Analyzer). While software is involved in image acquisition and analysis, it is integral to a system that includes significant hardware and chemical components.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The intended use explicitly states that the kit is "intended for the enumeration of circulating tumor cells (CTC)... in whole blood." It also states that the test is to be used "as an aid in the monitoring of patients with metastatic breast cancer." This clearly indicates that the device is used to examine specimens derived from the human body (whole blood) to provide information for the diagnosis, monitoring, or treatment of a disease (metastatic breast cancer).
- Device Description: The description details reagents and a system used to process and analyze a biological sample (whole blood) to identify and count specific cells (CTC).
- Clinical Data: The provided clinical data demonstrates the device's performance in a clinical setting, correlating CTC counts with clinical outcomes (progression-free survival and overall survival) in patients with metastatic breast cancer. This further supports its use in a diagnostic or monitoring context.
The definition of an In Vitro Diagnostic (IVD) device generally includes reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. This device fits that definition by providing information from a blood sample to aid in monitoring patients with metastatic breast cancer.
N/A
Intended Use / Indications for Use
The CellSearch™ Circulating Tumor Cell Kit is intended for the enumeration of circulating tumor cells (CTC) of epithelial origin (CD45-, EpCAM+, and cytokeratins 8, 18+, and/or 19+) in whole blood.
The presence of CTC in the peripheral blood, as detected by the CellSearch™ Circulating Tumor Cell Kit, is associated with decreased progression free survival and decreased overall survival in patients treated for metastatic breast cancer. The test is to be used as an aid in the monitoring of patients with metastatic breast cancer. Serial testing for CTC should be used in conjunction with other clinical methods for monitoring breast cancer. A CTC count of 5 or more per 7.5 mL of blood at any time during the course of the disease is predictive of shorter progression free survival and overall survival.
Product codes
NQI
Device Description
The CellSearch™ Circulating Tumor Cell Kit contains a ferrofluid-based capture reagent and immunofluorescent reagents. The ferrofluid reagent consists of nanoparticles with a magnetic core surrounded by a polymeric layer coated with antibodies targeting the EpCAM antigen for capturing CTC. After immunomagnetic capture and enrichment, fluorescent reagents are added for identification and enumeration of CTC. The fluorescent reagents include the following: anti-CK-Phycoerythrin (PE) specific for the intracellular protein cytokeratin (characteristic of epithelial cells),
DAPI which stains the cell nucleus, and anti-CD45-Allophycocyanin (APC) specific for leukocytes.
The reagent/sample mixture is dispensed by the CellTracks AutoPrep® System into a cartridge that is inserted into a MagNest® cell presentation device. The strong magnetic field of the MagNest® device attracts the magnetically labeled epithelial cells to the surface of the cartridge. The CellTracks® Analyzer II or CellSpotter® Analyzer automatically scans the entire surface of the cartridge, acquires images and displays any event to the user where CK-PE and DAPI fluorescence are co-located. Images are presented to the user in a gallery format for final classification. An event is classified as a tumor cell when its morphological features are consistent with that of a tumor cell and it exhibits the phenotype EpCAM+, CK+, DAPI+ and CD45-.
Mentions image processing
Yes
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
Not Found
Intended User / Care Setting
Not Found
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies
Non-clinical data:
Recovery: Blood samples from 5 healthy donors were spiked with cultured breast cancer cells (SK-BR-3) at concentrations of approximately 1300, 325, 81, 20, and 5 cells per 7.5 mL. These samples were processed, and CTC counts were determined. Linear regression analysis showed a recovery of 93% (Y=0.93x + 3.87 with R2=0.999).
Linearity / Reportable Range: Analysis of dilution series data (after factoring out percent recovery) demonstrated linearity over the reportable range of 0 to 1238 tumor cells, with a slope of 1.007 and R2 = 0.990.
Limits of Detection: 1 CTC per 7.5 mL can be detected.
Reproducibility:
a. System Reproducibility with CellSearch Circulating Tumor Cell Control: Three control samples (low and high concentration) were processed daily for over 30 days (n=99 each). Low: Mean cell count 48, Total Precision Standard Deviation 18% CV. High: Mean cell count 969, Total Precision Standard Deviation 5% CV.
b. System Reproducibility with Patient Samples: 163 duplicate samples from 47 patients were processed at multiple sites. Regression equation for duplicates was Y=0.98x + 0.67, R2=0.99. For CTC
§ 866.6020 Immunomagnetic circulating cancer cell selection and enumeration system.
(a)
Identification. An immunomagnetic circulating cancer cell selection and enumeration system is a device that consists of biological probes, fluorochromes, and other reagents; preservation and preparation devices; and a semiautomated analytical instrument to select and count circulating cancer cells in a prepared sample of whole blood. This device is intended for adjunctive use in monitoring or predicting cancer disease progression, response to therapy, and for the detection of recurrent disease.(b)
Classification. Class II (special controls). The special control for this device is FDA's guidance document entitled “Class II Special Controls Guidance Document: Immunomagnetic Circulating Cancer Cell Selection and Enumeration System.” See § 866.1(e) for availability of this guidance document.
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DEC 1 4 2006
Attachment 11 - Revised 510(k) Summary
510(k) SUMMARY
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) number is K062013.
| 807.92 (a)(1): Name: | Veridex, LLC |
|---|---|
| Address: | 33 Technology Drive |
| PO Box 4920 | |
| Warren, NJ 07059 | |
| Phone: | (908) 791-2438 |
| FAX: | (908) 791-2381 |
| Contact: | Debra J. Rasmussen |
| Worldwide Executive Director | |
| Regulatory and quality Affairs |
807.92 (a)(2): Device Name - trade name and common name, and classification
| Trade name: | CellScarch™ Circulating Tumor Cell Kit |
|---|---|
| Common name: | CellSearch™ Circulating Tumor Cell Kit |
| Classification: | Immunomagnetic Circulating Cancer Cell Selection |
| and Enumeration System, Class II, 21 CFR 866.6020. | |
| Product Code NQI, Immunology Devices- 82 |
- 807.92 (a)(3): Identification of the legally marketed predicate device
CellSearchTM Circulating Tumor Cell Kit, K050245
807.92 (a)(4): Device Description
The CellSearch™ Circulating Tumor Cell Kit contains a ferrofluid-based capture reagent and immunofluorescent reagents. The ferrofluid reagent consists of nanoparticles with a magnetic core surrounded by a polymeric layer coated with antibodies targeting the EpCAM antigen for capturing CTC. After immunomagnetic capture and enrichment, fluorescent reagents are added for identification and cnumeration of CTC. The fluorescent reagents include the following: anti-CK-Phycoerythrin (PE) specific for the intracellular protein cytokeratin (characteristic of epithelial cells),
1
DAPI which stains the cell nucleus, and anti-CD45-Allophycocyanin (APC) specific for leukocytes.
The reagent/sample mixture is dispensed by the CellTracks AutoPrep® System into a cartridge that is inserted into a MagNest® cell presentation device. The strong magnetic field of the MagNest® device attracts the magnetically labeled epithelial cells to the surface of the cartridge. The CellTracks® Analyzer II or CellSpotter® Analyzer automatically scans the entire surface of the cartridge, acquires images and displays any event to the user where CK-PE and DAPI fluorescence are co-located. Images are presented to the user in a gallery format for final classification. An event is classified as a tumor cell when its morphological features are consistent with that of a tumor cell and it exhibits the phenotype EpCAM+, CK+, DAPI+ and CD45-.
807.92 (a)(5): Intended use
The CellSearch™ Circulating Tumor Cell Kit is intended for the enumeration of circulating tumor cells (CTC) of cpithelial origin (CD45-, EpCAM+, and cytokeratins 8, 18+, and/or 19+) in whole blood.
The presence of CTC in the peripheral blood, as detected by the CellSearch™ Circulating Tumor Cell Kit, is associated with decreased progression frec survival and decreased overall survival in patients treated for metastatic breast cancer. The test is to be used as an aid in the monitoring of patients with metastatic breast cancer. Serial testing for CTC should be used in conjunction with other clinical methods for monitoring breast cancer. A CTC count of 5 or more per 7.5 mL of blood at any time during the course of the disease is predictive of shorter progression free survival and overall survival.
807.92 (a)(6): Technological Similarities and Differences to Predicate
There have been no material changes to the CellSearch™ Circulating Tumor Cell Kit; this 510(k) is being submitted for an expanded indications for use.
807.92 (b)(1): Brief Description of Non-clinical data
Recovery
Blood samples from a single healthy donor were pooled and five of six 7.5 mL aliquots were spiked with approximately 1300, 325, 81, 20, and 5 cultured breast cancer cells (SK-BR-3). The sixth tube was unspiked pooled blood and served as a zero point. These samples were processed on the CellTracks® AutoPrep System with the CellSearch™ Circulating Tumor Cell Kit and CTC counts were determined on the CellTracks®
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Analyzer II. The experiment was repeated for four additional donors. The observed cell counts were plotted against the results of the expected cell count. The results are summarized in Table 1.
| Expected Tumor Cell
Count | Mean Observed Tumor Cell
Count | Range of Percent Recovery |
|------------------------------|-----------------------------------|---------------------------|
| 1300 | 1215 | 91 to 95% |
| 325 | 308 | 82 to 101% |
| 81 | 85 | 80 to 136% |
| 20 | 22 | 95 to 140% |
| 5 | 7 | 120 to 200% |
Table 1. Percent Detection Estimates.
To determine the overall, or least squares fit, for the comparison of the observed and expected cell counts across all the data, lincar regression analysis was performed. The regression equation for these 30 samples was Y=0.93x + 3.87 with an R2=0.999 (R=0.999). The results of this study indicate that on average, over the tested CTC range, the recovery, as derived from regression analysis, is 93%.
Given the linear response of the tumor cell counts, one would expect the slope of the observed versus expected plot to be 1.0. However, the slope was 0.93. This is because the CellTracks® AutoPrep System with CellScarch™ CTC Kit involves the capture and fluorescent labeling of cells followed by their detection and enumeration by the CellTracks® Analyzer II. The loss of cells could therefore be attributed to one of the following possibilities; 1) the recovery of only 93% of the tumor cells spiked into 7.5mL of blood by the CellTracks® AutoPrep System, 2) the detection of only 93% of the tumor cells present in the sample chamber by the CellTracks® Analyzer II or 3) a combination of both of these sources of error.
Linearity / Reportable Range
Another way to examine the previous data is to analyze it as a dilution series to evaluate test linearity. We removed the confounding variable of percent recovery by using the observed value of the initial sample in the dilution series (i.e. the first tube) divided by the dilution factors to determine the expected values for the dilution series for each patient sample. Regression of all of these numbers of observed tumor cells versus the numbers of expected tumor cells yielded a slope of 1.007, an intercept of 3.0, and an R2 = 0.990 (R = 0.995). Therefore, once the percent recovery (cell loss) was factored out of the CTC values of each of the initial samples, the analysis of the data demonstrated that the detection of
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CTC was linear over the reportable range of 0 to 1238 tumor cells.
Limits of Detection
One CTC per 7.5 mL can be detected by the CellTracks® Analyzer II resulting in a limit of detection of 1 CTC in a cartridge. Linear regression shows that on average, 93% of CTC present in a 7.5 mL blood sample are recovered using the CellTracks® AutoPrep System (see Recovery section). The loss of approximately 7% of the CTC in the sample is not sufficient to reduce the limit of detection of 1 CTC.
Reproducibility:
a. System Reproducibility with CellSearch™ Circulating Tumor Cell Control
Three separate CellSearch™ Circulating Tumor Cell Control samples were prepared and processed each day for over 30 days, per the long run method of NCCLS guideline EP5-A2. Each single-use sample bottle contains a low and a high concentration of cells from a fixed cell line that have been pre-stained with two different fluorochromes. Summary statistics for the high and low control cells is presented below.
Table 2. Summary of Precision Analyses
| Low | High | |
|---|---|---|
| N | 99 | 99 |
| Mean cell count | 48 | 969 |
| Total Precision Standard | ||
| Deviation (ST) % CV | 18% | 5% |
b. System Reproducibility with Patient Samples
A total of 163 duplicate samples were collected from 47 patients over the course of the clinical study. These samples were processed at multiple sites to determine the reproducibility of CTC measurements. The regression equation for the comparison of these 163 duplicate samples was Y=0.98x + 0.67, R2=0.99. Table 3 shows the summary of the data for replicates where the average of the two CTC results was 5.
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Table 3. Reproducibility of CTC Counts in Duplicate Samples (n=163) w/Average of 5 CTC per 7.5 mL of blood.
| | CTC As illustrated in Figure 2 and Table 6, patients with elevated CTCs (≥5 CTC/7.5mL whole blood) at any of the time points had a much higher likelihood of rapid progression than did those with *p-values not adjusted for multiple hypothesis tests
Figure 3 shows that patients with ≥5 CTCs at all time points (Group 4) had the shortest median PFS, which was significantly different compared to the median PFS of Croup 3, Group 2, and Group 1. Differences between the curves for the other groups in this figure were not significant.
Overall Survival (OS) Analysis
OS Analysis Using Baseline CTC Results
Death occurred in 109 (62%) of the 177 patients, with a mean follow-up time for the 68 (38%) patients still alive of 22.7 ± 9.4 months (median = 21.1, range = 4.4 -- 48.6). At the time of these analyses, 44 (49%) of 89 patients from Favorable group (45) | 6.4 (3.0 to 10.9) | 35) | 11.3 (2.0 to 22.9) | 0.0021 |
Predictive Value of CTC Reduction or Increase on OS Elapsed OS times were calculated from the baseline blood draw. For Kaplan-Meier analysis (Figure 6), patients were segmented into four groups based on their CTC counts:
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- · Group 1 (green curve), 83 (47%) patients with 5 CTCs at baseline and =5 CTCs at all time points. The median overall survival (OS) in months with 95% confidence intervals is provided for each group, along with the number of patients (N) and percentage in each group.
*p-values not adjusted for multiple hypothesis tests
Figure 6 shows that patients who exceed the threshold of 5 CTCs at any point after the initiation of therapy are at a significantly higher risk of dying sooner. Patients with ≥5 CTCs at all time points (Group 4) had the shortest median OS, which was significantly different compared to the
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median OS of - 1 - 1 - 1 - 1 , Group 2, and Group 1 . The difference in the median survival between and Group I was also significant, and although the median OS for = while was shorter compared to Group 2, the difference was not statistically significant. Figure 6 also shows that patients who have ≥5 CTCs at baseline but eventually decrease to 5 | 5 | 25% increase in the sum of all lesions or appearance of a new measurable or non-measurable lesion. Partial response was defined as a decrease in the sum of all lesions of >50% and no new lesions.
- Radiology interpretations from the two expert radiologists were . classified as followed:
-
S and PR were considered to both reflect non-progressive disease (NPD)
-
PD was considered to reflect progressive disease
- In situations where one of the radiologists rendered a classification A of Indeterminate (I) but the other radiologist rendered a classification of S, PR or PD, the classification of the latter radiologist was used for comparison to CTCs (n=11)
-
When both radiologists rendered a classification of Indeterminate (I), then the data was not used in the comparison to CTCs (n=3)
-
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- خ A third independent radiologist adjudicated disagreements between the two primary readers regarding PD and NPD (n=27)
- In situations where the third independent radiologist rendered a ﺮ ﺍ classification of Indeterminate (I), the data was not used in the comparison to CTCs (n=2)
- In scrial imaging studies, radiology results that were less than one را month from a previous tabulated observation were not used (1=1).
- The CTC results obtaincd within ± one month of the imaging study . were classified as 5 CTCs with PD imaging response. The median OS in months (95% C.I.) for groups 1, 2, and 4 were 23.8 (20.5 to 31.6), 19.9 (12.5 to 23.6), and 6.4 (3.5 to 12.9), respectively.
*p-values not adjusted for multiple hypothesis tests
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VARIABILITY OF CTC AND RADIOLOGICAL ASSESSMENTS
CTCs
Inter-reader variabilities for the CTC counts at the first follow-up blood draw was determined by counting the number of instances where the operator at the testing site was not in concordance with the central laboratory in classifying a sample as ≥5 CTCs versus